Covalent catalysis aldol reactions

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

Aldolase is an example of an enzyme that uses electrophilic covalent catalysis. The amine of an active site lysine forms an imine (Section 10.5.2) with the carbonyl of fructose-1,6-bisphosphate. This more reactive imine electron sink allows a reverse aldol reaction to occur via the less basic enamine rather than the more basic enolate ion. Tautomerization of the resulting enamine to an imine, then hydrolysis, releases DHAP and returns the enzyme active site lysine to the free anime, ready for the next cycle. 

With respect to the covalent activation in conjugate additions, the catalyst, usually a primary or a secondary amine, can reversibly form a chiral enamine [ 11 ] to activate the nucleophile (D, Fig. 2.2) or a chiral iminium ion [12] to activate the acceptor (E, Fig. 2.2). The detection of enamine intermediates in asymmetric oiganocatalysis has been for a long time the missing piece of evidence for the commonly accepted mechanism of enamine catalysis. This gap has been recently solved with the first detection and structnral characterization of enamine intermediates in proUne-cata-lyzed aldol reactions by real-time NMR spectroscopy [13] and the direct observation of an enamine intermediate in the crystal strnctnre of an aldolase antibody [14]. 

Asymmetric catalysis is an important technique for the synthesis of chiral compounds. The introduction of supported IL catalyst into the field of asymmetric catalysis might offer new approaches to improve the catalytic performance and also the reusabiUty of chiral catalysts. The first example of a supported IL asymmetric catalyst is the proUne-catalyzed aldol reaction [116]. In this work, the IL molecule covalently attached to modified silica gel was used as the support for IL-phase containing L-proUne. The modification of the silica gel surface by the IL molecule is crucial to gain high enantioselectivity. In the model reaction of acetone and benzaldehyde, the yield to 4-hydroxy-4-phenylbutan-2-one was 51% with 64% ee. Otherwise, the yield was only 38% with 12% ee without the silica gel modification. 

As detailed in Sections 42.2 and 42.3, both covalent and non-covalent organocatalytic activation modes have provided efficient strategies to design asymmetric MCRs. A quite recent study by Zhou and list has demonstrated the feasibility of combining asymmetric Bronsted acid catalysis with aminocatalysis to design even more sophisticated reaction sequences toward the synthesis of useful complex molecules. Specifically, they developed a highly enantioselective approach to pharmaceutically relevant 3-substituted cyclohexylamines from 2,6-diketones 223 via an aldolization/dehydration/conjugate reduction/reductive amination domino... 

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